Alzheimer's disease (AD) is one of the most significant public health problems of the 21st century with the number of patients in the US estimated to reach 11--16 million by 2050 and an annual cost of care projected to reach $1.1 trillion. Current treatments for the disease, including cholinesterase inhibitors and memantine, have limited effect for a short duration. There is a pressing need to develop better therapies to relieve the cognitive impairments of the disease, reduce the cost of care, and delay the institutionalization of AD patients. The goal of the proposed studies is to test novel, selective HDAC2 inhibitors for their potential in treating AD. Rodin Therapeutics has compounds that were identified using biochemical and cell based assays for both potency to inhibit HDAC2 activity, weaker or no activity on other class I HDACs, and high residence time on HDAC2 vs HDAC1. The combination of potency and high residence time on HDAC2 has led to the identification of a unique chemical series of compounds selective for HDAC2 with drug--like properties suitable for in vivo work. Here, we propose studies for efficacy to reverse the inhibition of synaptic function in a murine model of neurodegeneration. Further, we propose to demonstrate that HDAC2 selective inhibitors are free of the toxicity associated with currently available non--selective Class I HDAC inhibitors. The proposed project will demonstrate that newly discovered small molecule inhibitors of HDAC2 will not affect hematopoesis, a side effect associated with liabilities of pan Class I HDAC inhibitors (e.g. CI--994, SAHA, entinostat) and yet effectively upregulate synaptic genes associated with cognitive function and improve cognitive behavior. A novel HDAC2 inhibitor with the desired profile of cognitive enhancement, upregulation of synaptic gene and no effect on hematopoietic endpoints would confirm that selective HDAC2 inhibitors have a wider therapeutic index than pan--class I HDAC inhibitors currently available. At the successful conclusion of this Phase 1 SBIR, we will be poised to select a compound to move forward into IND-- enabling studies to support human clinical trials. Phase2 of the SBIR proposal will fund GLP toxicity studies in two species. The proposed studies align with the mission of the institute to develop improved treatments for individuals with age--related cognitive dysfunction secondary to Alzheimer's disease.